Photo of Longxing Cao

Biotechnology & medicine

Longxing Cao

Developing de novo protein design methods as the next-generation therapeutics to regulate immune response and kill viruses.

Year Honored

Westlake University

Asia Pacific

Hails From
Asia Pacific

Molecular recognition is central to biology, and high-affinity binding proteins now play an essential role in the pharmaceutical industry. However, existing protein-based drugs are mainly based on the engineering of naturally existing proteins or monoclonal antibodies (mAbs), which are usually quite unstable and can only tolerate a limited number of modifications; thus therapeutic proteins developed from natural proteins frequently suffer from poor stability, manufacturability, and in many cases, significant immunogenicity. 

Longxing Cao has developed a method to design de novo proteins to bind to a specific site on the surface of a protein using no information other than the three-dimensional structure of the target.

These de novo proteins do not ever exist in nature, and they are designed based on basic physical and chemical principles using computers. The de novo proteins can be precisely crafted as novel drugs, catalysts, and materials to address the 21st-century challenges in medicine, energy, and technology.

To demonstrate his work, Longxing Cao and colleagues designed binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders are hyperstable and bind their targets with nanomolar to picomolar affinities, and for the five proteins that were able to crystallize, the computational models of the bound complexes closely match the crystal structures. This new method enables the targeted design of binders to sites of interest on a wide variety of proteins for diagnostics and therapeutics applications. There are several advantages of these de novo binders compared to the usual antibodies-based therapies and diagnostic tools, such as high stability, low cost of expression, and highly controllable modifications. These de novo mini-protein binders have a great potential to be used as the next-generation therapeutic drugs and diagnostic tools.

During the Covid-19 pandemic, Longxing Cao successfully designed mini protein inhibitors that could bind with picomolar affinity to the SARS-CoV-2 Spike protein and prevent the virus from infecting cells.

Unlike neutralizing antibodies, the de novo inhibitors are designed against the most conserved region of the virus spike protein without being distracted by immune dominant epitopes; they retain high potency to the existing pandemic variants and are most likely to be resilient to future changes. These inhibitors can be manufactured cheaply and administered directly into the respiratory system as prophylactics and therapeutics.